Cyclic nucleotide gated cation channels (CNG) are a class of non-selective cation channels that are opened by direct binding of cyclic nucleotides such as cGMP and cAMP. CNG channels are highly permeable to Na+ and Ca2+, and their activation leads to depolarization and increases in internal Ca2+ concentrations. These channels can link changes in cytoplasmic cyclic nucleotide levels to changes in cellular excitability, secretion of neurotransmitters and the stimulation of calcium-dependent pathways.
CNG family channel proteins are multimers and can be formed by at least two functionally distinct classes of subunits. The two classes of subunits, alpha and beta, share a common motif of 6 transmembrane domains, a pore motif and a cytoplasmic cyclic nucleotide binding domain (Finn et al, Annu. Rev. Physiol. 58:395–426:1996). CNG alpha subunits can form functional channels as homomultimers, i.e., all subunits contributing to the channel pore are identical. Beta subunits, in contrast, can only form functional channels when expressed with an alpha subunit. These heteromultimeric channels show functional properties consistent with native CNG channels (Gerstner, A., et al, J. Neurosci. 20(4):1324–1332, 2000; Finn J T, et al, Annu. Rev. Physiol. 58:395–426, 1996). For example, coexpression of alpha and beta subunits occurs in retinal rod cells where the alpha subunit CNGA1 forms a heteromultimer with the beta subunit CNGB1 (CNG4) (Gerstner, A., et al, J. Neurosci. 20(4):1324–1332, Feb. 15, 2000).
CNG channels are important for sensory signal transduction in retinal and olfactory and taste bud cells in response to primary sensory stimuli such as light and aerosolized or dissolved molecules (Ding, C, et al, Am. J. Physiol. 272 (Cell Physiol. 41): C1335–C1344, 1997). In photoreceptor cells, CNG channels are open in darkness due to a high basal concentration of cGMP. This causes a tonic depolarization of the membrane and constitutive neurotransmitter release. Upon stimulation by light, cGMP levels drop, closing the CNG channels. This in turn causes a hyperpolarization of the membrane, a drop in the internal Ca2+ concentration, and a decrease in the release of neurotransmitter (Finn, J T, et al, Annu. Rev. Physiol. 58:395–426, 1996).
CNG channels have been found in a number of tissues, suggesting that these channels may link a variety of stimuli to changes in membrane potential and cytoplasmic calcium levels (Ding, C, et al, Am. J. Physiol. 272 (Cell Physiol. 41):C1335–C1344, 1997; Kingston P, Synapse 32:1–12, 1999). For instance, retinal and olfactory CNG channels are expressed in various parts of the brain (Ding, C, et al, Am. J. Physiol. 272 (Cell Physiol. 41):C1335–C1344, 1997; Kingston P, Synapse 32:1–12, 1999). Because these channels are highly permeable to Ca2+, they may stimulate Ca2+-dependent pathways that have significant effects on neuronal activity. More directly, they may contribute to neuronal activity by providing excitatory depolarizations. CNG channels may also interact with other second messenger systems such as the Nitric Oxide-pathway to provide the longer lasting changes that are important mechanisms in learning and memory (Kingston P, Synapse 32:1–12, 1999). CNG channels have been found in the testis, and through the regulation of the internal Ca2+ concentration, may be involved in chemotaxis of sperm (Weyand, I., et al, Nature 368:859–863, 1994). Expression of CNG channels has also been noted in heart, aorta and kidney, where they may play a role in the regulation of heart rate, blood pressure and electrolyte transport, respectively (Finn et al., Ann. Rev. Physiol. 1996, 58:395–426). The full scope of CNG channel function is not yet entirely understood, but it is clear that they play a key role in many physiological processes.